and specific aims): Contraction of airway smooth muscle causes airway obstruction and relaxation of this muscle is the principal action of beta-adrenergic agonists used to treat asthma. Calcium ion is an important second messenger that contributes to the determination of tension in smooth muscle. The application hypothesizes that the cytosol is not homogeneous with respect to calcium concentrations. There are calcium influx pathways into the cell that are not major determinants of (Ca2+)i and, therefore, not major determinants of tension. Both beta-adrenergic and muscarinic agonists stimulate calcium influx at the cell periphery in order to maintain sarcoplasmic reticulum (SR) calcium stores, but the two different agonists have opposite effects on (Ca2+)i.
The specific aims are to 1) determine how beta-adrenergic agonists decrease (Ca2+)i; 2) determine whether beta-adrenergic agonists stimulate calcium influx pathways that have minimal effects on (Ca2+)i because of SR uptake refilling processes; 3) during muscarinic stimulation, determine whether the calcium content of the SR regulates calcium influx; 4) during sustained muscarinic stimulation, determine whether calcium influx occurs via multiple pathways, one of which is a minor determinant of (Ca2+)i because of SR uptake and refilling processes; and 5) characterize the detection of calcium at the cell periphery using specific fura-2 AM loading conditions.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL054143-03
Application #
2378841
Study Section
Lung Biology and Pathology Study Section (LBPA)
Project Start
1995-04-01
Project End
1998-02-28
Budget Start
1997-03-01
Budget End
1998-02-28
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
660735098
City
Worcester
State
MA
Country
United States
Zip Code
01655
Martin, Gilles; O'Connell, Robert J; Pietrzykowski, Andrzej Z et al. (2008) Interleukin-4 activates large-conductance, calcium-activated potassium (BKCa) channels in human airway smooth muscle cells. Exp Physiol 93:908-18
Ethier, Michael F; Madison, J Mark (2006) Adenosine A1 receptors mediate mobilization of calcium in human bronchial smooth muscle cells. Am J Respir Cell Mol Biol 35:496-502
Ethier, Michael F; Madison, J Mark (2006) IL-4 inhibits calcium transients in bovine trachealis cells by a ryanodine receptor-dependent mechanism. FASEB J 20:154-6
Ethier, Michael F; Cappelluti, Erika; Madison, J Mark (2005) Mechanisms of interleukin-4 effects on calcium signaling in airway smooth muscle cells. J Pharmacol Exp Ther 313:127-33
Madison, J Mark (2003) Migration of airway smooth muscle cells. Am J Respir Cell Mol Biol 29:8-11
Ethier, M F; Madison, J M (2002) LY294002, but not wortmannin, increases intracellular calcium and inhibits calcium transients in bovine and human airway smooth muscle cells. Cell Calcium 32:31-8
Ethier, M F; Yamaguchi, H; Madison, J M (2001) Effects of cyclopiazonic acid on cytosolic calcium in bovine airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 281:L126-33
Madison, J M; Ethier, M F (2001) Interleukin-4 rapidly inhibits calcium transients in response to carbachol in bovine airway smooth muscle cells. Am J Respir Cell Mol Biol 25:239-44
Ethier, M F; Dextradeur, T; Schaefer, O P et al. (2000) Effects of salmeterol on muscarinic inhibition of adenylyl cyclase in bovine trachealis cells. Life Sci 67:2753-8
Madison, J M; Ethier, M F; Yamaguchi, H (1998) Refilling of caffeine-sensitive intracellular calcium stores in bovine airway smooth muscle cells. Am J Physiol 275:L852-60

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